The use of more intensive antiretroviral therapies, such as HAART, in the treatment of HIV infection has led to a marked reduction in morbidity and mortality associated with AIDS. This happens because the incidence of the major opportunistic infections and of many AIDS-related neurological disorders dramatically decreased, but the Progressive Multifocal Leukoencephalopathy (PML) is still observed with a prevalence up to 5% in AIDS patients. Although the advent of HAART did not affect so much the incidence of PML, some changes in the clinical course of this fatal disease have been observed. In fact PML usually results in death within 3-6 months of diagnosis (PML fast progressing patients), but to date there are reports of remission of PML during HAART and several PML cases have prolonged rate of survival, up to one year from the onset of the disease (PML slow progressing patients). In this project we are hypothesizing that either a particular JCV genotype or a specific TCR rearrangement or both could affect the disease progress, slowing down the process of demyelination. Moreover several cases suffering with a PML-like Leukoencephalopathy, called non- determined Leukoencephalopathy (NDLE) with no evidence of JCV genome in CSF have been lately reported. Our suggestion is that the result of an improved immune status upon HAART could also lead to an imbalanced expression of cytokines and immunomodulators by peripheral lymphocytes that may affect. In order to verify our hypothesis and better understand the etiology, the development and the progress of the new variant of PML and of the novel JCV negative-leukoencephalopathy, we are proposing to enroll in a longitudinal study, patients affected with fast and slow progressing PML, patients with suspected NDLE, HIV+ patients without any neurological disorders and healthy controls, whose biological samples will be collected at different times of the diseases and subjected to immunological, virological, genetic conventional and innovative examinations as described in the proposal. [unreadable] [unreadable]